In this renewal application we propose to focus on the theme of plasticity in the aged brain, its regulatory mechanisms, and cellular and molecular cascades. We propose that brain plasticity mechanisms operating through cellular and molecular cascades can offset losses and maintain brain function as the organism ages. Ironically, however, these same cascades can become part of the process driving brain pathology. In this program project we propose to examine the operation of select pathways which our data and others point toward as critical to this intersection between brain plasticity and age-related pathology. Research will focus on three molecular systems pivotal to the aged brain: beta-amyloid (Abeta) and amyloid precursor protein (APP), specific proteases and protease inhibitors, add certain key neurotrophic factors. These systems can aid in brain maintenance, generate pathological cascades, and in some cases, perhaps intersect to generate new cascades. We will examine these cascades with the goal of identifying key intervention points which can aid in the maintenance of brain function. In order to evaluate such multifactorial cascades we need a team approach comprised of experts in their respective specialties so that we can identify the critical mechanisms and intervention points and learn to control them. In the study of APP/Abeta, Dr. Glabe will examine the regulation of Abeta production and its actions on cerebral vascular smooth muscle cells, and Dr. Lynch will examine the influence of lysosomal impairment on Abeta/APP and synaptic function usign long-term organotypic hippocampal cultures. Dr. Cunningham will focus on thrombin and protease nexin-1 and their autodestructive versus autoprotective actions on neurons and glia. Drs. Cotman and Gall will focus on growth factor cascades that are induced after injury and that are postulated to occur in the aged and Alzheimer brain as, for example, in senile plaque formation. It is hypothesized that such cascades can, in turn, influence Abeta/APP and reciprocally, Abeta can enter the cascades and drive the course of functional plasticity toward dysfunction and neurodegeneration. Among the various projects, numerous collaborations exist. A central theme of our proposal is the development of a better understanding of the normal aging process. Accordingly, we propose to maintain and build a core facility to increase the acquisition of qualitity postmortem brain tissues from healthy individuals as well as expand the collection of AD and vascular dementia tissues. This core will also assist in the preparation of peptides for program investigations.